Interactions of Emerging Bunyaviruses with Host Cells

新兴布尼亚病毒与宿主细胞的相互作用

• 批准号: 7670061
• 负责人: Robert W. Doms
• 金额: $ 33万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670061
• 关键词: Abortion Rates; Acute; Africa; Andes Virus; Antibodies; Antiviral Agents; Biological Assay; Bunyaviridae; Case Fatality Rates; Categories; Cell Communication; Cells; Centers for Disease Control and Prevention (U.S.); Cherry - dietary; Codon Nucleotides; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Culicidae; Databases; Development; Disease Outbreaks; Domestic Animals; Economics; Emerging Communicable Diseases; Family; Fever; Funding; Genes; Genetic; Genome; Genus Phlebovirus; Goals; Grant; Hantavirus; Hantavirus Pulmonary Syndrome; Hemorrhagic Fever with Renal Syndrome; Hepatic; Human; Infection; Insecta; Kenya; Libraries; Mammalian Cell; Nairovirus; Orthobunyavirus; Pathway interactions; Pennsylvania; Puumala virus; RNA Interference; Reagent; Request for Applications; Research Personnel; Retinal; Rift Valley fever virus; Rodent; Screening procedure; Series; Sin Nombre virus; Symptoms; Testing; Therapeutic; Therapeutic Intervention; United States Department of Agriculture; Universities; Vaccines; Viral; Virus; Virus Replication; Work; base; biodefense; cell type; cellular targeting; high throughput technology; member; pathogen; small molecule; small molecule libraries; tool

The family Bunyaviridae consists of over 300 viruses with members of four Bunyaviridae genera (Hantavirus, Orthobunyavirus, Phlebovirus and Nairovirus) infecting humans. A number of the Hantaviruses and Rift Valley Fever virus (RVFV, a Phlebovirus) are Category A agents with RVFV being of particular concern. RVFV, which is spread by infected mosquitoes, was first described in Kenya in 1931 and has since been documented throughout much of Africa and the Arabian peninsula. RVFV causes acute fevers and, sometimes, retinal or hepatic complications with hemorrhagic symptoms. A recent outbreak in Kenya had a case-fatality rate of greater than 20% for those with severe illness. In addition, RVFV causes catastrophic abortion rates in domesticated animals, and thus can causes significant economic losses. As a result, it is categorized as an overlap select agent by both the CDC and the US Department of Agriculture. Also of concern are a number of Hantaviruses that cause hantavirus pulmonary syndrome (HPS) and/or hemorrhagic fever with renal syndrome (HFRS) in humans. Included among these rodent-borne viruses are Sin Nombre virus, Andes virus, and Puumala virus. RVFV and hantaviruses are under-studied pathogens for which there are no approved vaccines or therapeutics. With support from the MARCE beginning in 2005, we launched an effort to study RVFV and, more recently, several hantaviruses. Working with colleagues at USAMRIID, the CDC and at Penn, we have developed a series of genetic tools and functional assays that are being used in high throughput, whole genome RNAi and chemical library screens to identify host cell molecules and pathways needed for the replication and dissemination of these viruses. Significant progress with RVFV has already been made. By studying several bunyaviruses, we hope to identify cellular pathways that are common to this virus family, as well as to identify cellular molecules that are uniquely important to specific viral agents. The overall goal of our project is to identify host cell targets for therapeutic intervention. Specifically, we propose to: 1. Complete our whole genome RNAi and chemical library screens with RVFV, validate hits and determine mechanism of action. 2. Develop the genetic tools, assays and reagents needed to perform whole genome RNAi and chemical library screens for Sin Nombre virus. 3. Determine breadth of action by testing against Andes and Puumala.

布尼亚病毒科由超过300种病毒组成，其成员为布尼亚病毒科的四个属（汉坦病毒， 正布尼亚病毒、白蛉病毒和内罗病毒）感染人类。一些汉坦病毒和裂谷病毒 谷热病毒（RVFV，一种白蛉病毒）是A类病原体，其中RVFV特别令人关注。 RVFV由受感染的蚊子传播，于1931年首次在肯尼亚被描述，此后一直被 在非洲和阿拉伯半岛的大部分地区都有记载。RVFV引起急性发热， 有时，视网膜或肝脏并发症伴有出血症状。最近在肯尼亚爆发的一场疫情 重症患者病死率超过20%。此外，RVFV还造成灾难性的 这可能会导致家畜流产率上升，从而造成重大经济损失。因此， 被CDC和美国农业部归类为重叠选择剂。评价很 令人担忧的是许多引起汉他病毒肺综合征（HPS）和/或 肾综合征出血热（HFRS）。这些啮齿动物传播的病毒包括 Sin Nombre病毒、安第斯山脉病毒和普马拉病毒。RVFV和汉坦病毒是研究不足的病原体 目前还没有批准的疫苗或治疗方法。在2005年开始的农业和农村经济改革委员会的支持下， 我们开始了对RVFV的研究，最近又开始了对几种汉坦病毒的研究。与同事一起工作， USAMRIID，CDC和宾夕法尼亚大学，我们已经开发了一系列遗传工具和功能测定， 正在用于高通量、全基因组RNAi和化学文库筛选以鉴定宿主细胞 这些病毒复制和传播所需的分子和途径。重大进展 RVFV已经有了。通过研究几种布尼亚病毒，我们希望能够确定细胞途径 这是共同的病毒家族，以及确定细胞分子，是独特的重要， 特定的病毒因子。我们项目的总体目标是确定治疗干预的宿主细胞靶点。 具体而言，我们建议： 1.用RVFV完成我们的全基因组RNAi和化学文库筛选，验证命中， 确定作用机制。 2.开发进行全基因组RNAi所需的遗传工具、测定和试剂， 化学库筛选辛农布尔病毒 3.通过对安第斯山脉和普马拉的测试来确定行动的广度。